Junctional Neurulation: A Unique Developmental Program Shaping a Discrete Region of the Spinal Cord Highly Susceptible to Neural Tube Defects

Abstract

In higher vertebrates, the primordium of the nervous system, the neural tube, is shaped along the rostrocaudal axis through two consecutive, radically different processes referred to as primary and secondary neurulation. Failures in neurulation lead to severe anomalies of the nervous system, called neural tube defects (NTDs), which are among the most common congenital malformations in humans. Mechanisms causing NTDs in humans remain ill-defined. Of particular interest, the thoracolumbar region, which encompasses many NTD cases in the spine, corresponds to the junction between primary and secondary neurulations. Elucidating which developmental processes operate during neurulation in this region is therefore pivotal to unraveling the etiology of NTDs. Here, using the chick embryo as a model, we show that, at the junction, the neural tube is elaborated by a unique developmental program involving concerted movements of elevation and folding combined with local cell ingression and accretion. This process ensures the topological continuity between the primary and secondary neural tubes while supplying all neural progenitors of both the junctional and secondary neural tubes. Because it is distinct from the other neurulation events, we term this phenomenon junctional neurulation. Moreover, the planarcell-polarity member, Prickle-1, is recruited specifically during junctional neurulation and its misexpression within a limited time period suffices to cause anomalies that phenocopy lower spine NTDs in human. Our study thus provides a molecular and cellular basis for understanding the causality of NTD prevalence in humans and ascribes to Prickle-1 a critical role in lower spinal cord formation.

New classification of spinal lipomas based on embryonic stage

“…The new concept of junctional neurulation bridging primary and secondary neurulation can explain the development of complex forms of spinal lipoma, such as the chaotic spinal lipoma in Pang's classification. 4,16,20 The formation of a spinal lipoma can be conceived as a continuous process crossing the juncture between primary and secondary neurulation in some cases.…”

“…12 Recent studies suggest the presence of a unique process called "junctional neurulation," bridging the primary and secondary neurulations. 4 Presence of the junctional region between the primary and secondary neurulation has also been reported. 24 The complex process of caudal neural tube formation is also implicated in the development of various types of spinal lipomas.…”

Junctional Neural Tube Defect

“…As junctional neurulation proceeds from HH 8 to 12, these ventromedial cells become SOX-2 positive, suggesting neuronal differentiation. DiI microcrystal fluorescence tracking of cells at the NSB shows the dorsolateral cell population undergo dorsal folding followed by midline fusion as expected for primary neural tube closure, whereas the ventromedial cells migrate caudally to give rise to the secondary neural tube 10) . The medial SOX-2 negative cell population meanwhile express Snail-2, Bmp-4 and N-cadherin instead of E-cadherin, evidence of mesodermal progenitor cells undergoing epithelium-to-mesenchyme transition 9,24,42) .…”

Reply to the comments by Eibach et al.

“…It seems that the main point of discussion is the location of the primary and secondary neural tubes. Although the classic view puts the secondary neural tube at the lumbosacral region, the study which had elaborated the cellular and molecular features of the junctional neurulation proposed the idea that unlike the mouse, chick and human may have a wide range of the "junctional neural tube" corresponding to the thoracolumbar region in humans [2]. Hence, if the spatial extent of the junctional neurulation is modified to include up to the low thoracic region, the clinical and electrophysiological findings of the two cases stated in our study may not be interpreted as "unsuitable" for junctional neural tube defect (JNTD).…”